A chloroplast enzyme safeguards plants against pathological protein aggregation that causes Huntington’s and other neurodegenerative diseases / new research reported in “Nature Aging” may have found a way to “copy” the mechanism for application in human cells
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Researchers at the University of Cologne’s CECAD Cluster of Excellence for Aging Research and the CEPLAS Cluster of Excellence for Plant Sciences have found a promising synthetic plant biology approach for the development of a therapy to treat human neurodegenerative diseases, especially Huntington’s disease. In their publication “In-planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation” in Nature Aging, they showed that a synthetic enzyme derived from plants – stromal processing peptidase (SPP) – reduces the clumping of proteins responsible for the pathological changes in models of Huntington’s disease in human cells and the nematode Caenorhabditis elegans.
Huntington’s disease is among the so called polyglutamine (polyQ) diseases, a group of neurodegenerative disorders caused by multiple repetitions of glutamine amino acids in specific proteins. An excessive number of polyQ repeats can cause proteins to aggregate or accumulate in harmful and damaging protein deposits, leading to cellular dysfunction and death. To date, nine polyQ disorders have been described in humans. They all remain incurable. Among them, Huntington’s disease is an inherited condition that causes widespread deterioration in the brain and disrupts thinking, behavior, emotion and movement.
Plants are immune to harmful protein aggregation
In their recent study, Professor Dr David Vilchez (CECAD) and Dr Ernesto Llamas (CEPLAS) followed an unconventional approach to find potential drugs to treat polyQ diseases like Huntington’s. Plants are constantly challenged by the environment, but they cannot move to escape from these conditions. However, plants possess a striking resilience to stress that allows them to live long. Unlike humans who suffer from proteinopathies caused by the toxic aggregation or cluster of proteins, plants do not experience these kinds of diseases. They express hundreds of proteins containing polyQ repeats, but no pathologies from these factors have been reported. To explore how plants deal with toxic protein aggregation, Dr Ernesto Llamas, first author of the study, and colleagues introduced the toxic mutant protein huntingtin in plants, which causes cell death in human neurons. In contrast to animal and human models, they found that Arabidopsis thaliana plants actively removed huntingtin protein clumps and avoid harmful effects.
By means of synthetic biology, the scientists then transferred the plants’ ability to avoid aggregation into human cultivated cells and animal models of Huntington’s disease. Their hope is that the use of plant proteins could lead to new therapeutic approaches for treating Huntington’s disease and other neurodegenerative diseases.
“We were surprised to see plants completely healthy, even though they were genetically producing the toxic human protein. The expression of mutant huntingtin in other models of research like human cultured cells, mice and nematode worms induce detrimental effects and symptoms of disease,” said David Vilchez.
Plant protein alleviates symptoms in human cells and nematodes
The next step was to discover how plants avoided the toxic aggregation of mutant huntingtin. Indeed, the scientists discovered that the chloroplasts, the plant-specific organelles that perform photosynthesis, were the reason why plants do not show toxic protein deposits. Llamas said: “Unlike humans, plants have chloroplasts, an extra cellular type of organelle that could provide an expanded molecular machinery to get rid of toxic protein aggregates.”
The multidisciplinary team identified the chloroplast plant protein SPP as the reason why plants are unaffected by the problematic human protein. Producing the plant SPP in models of Huntington’s disease such as human cultured cells and worms like the nematode C. elegans reduced protein clumps and symptoms of disease. “We were pleased to observe that expression of the plant SPP protein improved motility of C. elegans worms affected by huntingtin even at later aging stages where the symptoms are even worse,” said Dr Hyun Ju Lee, a postdoc also involved in the study. The results thus open the door to testing SPP as a potential therapy for Huntington’s disease.
Plants as models for aging research
Llamas is convinced that plant research can make a meaningful contribution to treating human diseases. “Many people don’t notice that plants can persist amongst variable and extreme environmental conditions that cause protein aggregation. I believe that plant molecular mechanisms hold the key to discovering new drugs that can prevent human diseases. We usually forget that some plants can live thousands of years and should be studied as models of aging research.” Dr Seda Koyuncu, another postdoc involved in the study, added: “Over the past years, we have seen several promising approaches to treating hereditary diseases like Huntington’s fail. We are confident that our plant synthetic approach will lead to significant advances in the field.”
The team has since acquired funding form the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung – BMBF) through the GO-Bio initial program. “We want to bring our idea into an application. Our plan is to found a start-up to produce plant-derived therapeutic proteins and to test them as potential therapeutics to treat neurodegenerative diseases in humans,” said Llamas.
The research was conducted at the University of Cologne’s CECAD Cluster of Excellence in Aging Research and CEPLAS Cluster of Excellence on Plant Sciences.

A lower body temperature is one of the most effective mechanisms to prolong the lifespan of animals. Writing in ‘Nature Aging’, a working group at the University of Cologne’s CECAD Cluster of Excellence in Aging Research has now described precisely how this works. The scientists show that cold can prevent the pathological aggregation of proteins typical for two aging-associated neurodegenerative diseases.
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Cold activates a cellular cleansing mechanism that breaks down harmful protein aggregations responsible for various diseases associated with aging. In recent years, studies on different model organisms have already shown that life expectancy increases significantly when body temperature is lowered. However, precisely how this works has still been unclear in many areas. A research team at the University of Cologne’s CECAD Cluster of Excellence in Aging Research has now unlocked one responsible mechanism. The study ‘Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes’ has appeared in Nature Aging.
Professor Dr David Vilchez and his working group used a non-vertebrate model organism, the nematode Caenorhabditis elegans, and cultivated human cells. Both carried the genes for two neurodegenerative diseases which typically occur in old age: amyotrophic lateral sclerosis (ALS) and Huntington’s disease. Both diseases are characterized by accumulations of harmful and damaging protein deposits – so-called pathological protein aggregations. In both model organisms, cold actively removed the protein clumps, thus preventing the protein aggregation that is pathological in both ALS and Huntington’s disease.
More precisely, the scientists explored the impact of cold on the activity of proteasomes, a cellular mechanism that removes damaged proteins from cells. The research revealed that the proteasome activator PA28γ/PSME3 mitigated the deficits caused by aging in both the nematode and in the human cells. In both cases, it was possible to activate proteasome activity through a moderate decrease in temperature. “Taken together, these results show how over the course of evolution, cold has preserved its influence on proteasome regulation – with therapeutic implications for aging and aging-associated diseases” said Professor Vilchez.
Aging is a major risk factor for several neurodegenerative diseases associated with protein aggregation, including Alzheimer’s, Parkinson’s, Huntington’s and ALS. Professor Vilchez said: “We believe that these results may be applied to other age-related neurodegenerative diseases as well as to other animal species.” A key finding was that the proteasome activity can also be increased by genetic overexpression of the activator. That way, disease-causing proteins can be eliminated even at the normal body temperature of 37 degrees Celsius. These results may provide therapeutic targets for aging and aging-associated diseases.
It has long been known that while extremely low temperatures can be harmful to organisms, a moderate reduction in body temperature can have very positive effects. For example, a lower body temperature prolongs the longevity of cold-blooded animals like worms, flies or fish, whose body temperature fluctuates with the temperature of the environment. However, the same phenomenon also applies to mammals, who maintain their body temperature within a narrow range no matter how cold or warm their environment is. For example, the nematode lives much longer if it is moved from the standard temperature of 20 degrees Celsius to a colder temperature of 15 degrees Celsius. And in mice, a slight decrease in body temperature of just 0.5 degrees significantly extends their lifespan. This supports the assumption that temperature reduction plays a central role in longevity in the animal kingdom and is a well-conserved evolutionary mechanism.
Even in humans, a correlation between body temperature and lifespan has been reported. Normal human body temperature is between 36.5 and 37 degrees Celsius. While an acute drop in body temperature below 35 degrees leads to hypothermia, human body temperature fluctuates slightly during the day and even reaches a cool 36 degrees during sleep. Interestingly, a previous study reported that human body temperature has steadily declined by 0.03 degrees Celsius per decade since the Industrial Revolution, suggesting a possible link to the progressive increase in human life expectancy over the last 160 years.
The research was conducted at the University of Cologne’s CECAD Cluster of Excellence in Aging Research.